About Herbs

Bottom Line: So far, clinical trials show that d-limonene is NOT an effective cancer treatment.

D-limonene is derived from the peels of citrus fruits. Scientists are not exactly sure how it works, but it has shown anti-cancer activity in several laboratory studies. These studies suggest that D-limonene alters the signaling pathways within cancer cells in a way that halts the cancer cells as they divide and causes their death (apoptosis). In animals, D-limonene is able to slow the growth of pancreatic, stomach, colon, skin, and liver cancers. It has also shown the ability to slow the initial promotion of tumors and/or their progression in animals that have been exposed to carcinogens (cancer-causing substances). However, these anticancer effects have not been replicated in humans.

Cancer treatment:
Researchers conducted a two-part study to assess the effectiveness of D-limonene in treating solid tumors that had not responded to other therapies. In the first part, 32 patients with solid tumors received a range of doses of intravenous D-limonene in order to identify how high the doses could go without causing toxic side effects. Because one breast cancer patient showed a partial response (shrinkage of her tumor), ten additional breast cancer patients were added to the study and were given 8 g/m²/day of D-limonene. However, none of these patients showed any tumor shrinkage. This small study does not support d-limonene as a cancer treatment.

p-mentha-1,8-diene

R-limonene, orange peel oil, citrus peel oil, citrene

Derived from the peels of citrus fruits. Patients use this supplement to prevent and treat cancer. D-Limonene is a cyclic monoterpene that causes G1 cell cycle arrest, induces apoptosis, and inhibits posttranslational modification of signal transduction proteins. Following oral administration, D-limonene is rapidly metabolized to limonene-1,2-diol, perillic acid, dihydroperillic acid, and uroterpenol ^{(1) (2) (10)}. D-Limonene has a biologic half-life of approximately 24 hours, while its metabolites exhibit relatively short biologic half-lives of approximately 2 hours ⁽⁵⁾. Side effects include nausea, vomiting, and diarrhea ⁽¹⁾. A case report of contact dermatitis ⁽¹²⁾ has also been reported. In vitro and animal data suggest potential efficacy of D-limonene in treating cancer, but human data are lacking. Further research is necessary to determine if D-limonene has a role in the prevention or treatment of cancer.

The exact mechanism of action is unknown. D-Limonene and its metabolites, perillic acid, dihydroperillic acid, uroterpenol, and limonene1,2-diol, may inhibit tumor growth via inhibition of p21-dependent signaling and apoptosis resulting from induction of the transforming growth factor beta-signaling pathway ^{(4) (8)}. D-Limonene metabolites also cause G1 cell cycle arrest, inhibit posttranslational modification of signal transduction proteins, and cause differential expression of cell cycle- and apoptosis-related genes ⁽⁶⁾. Animal studies show activity of D-limonene against pancreatic, stomach, colon, skin, and liver cancers ⁽³⁾. Data also indicate that D-limonene slows the promotion/progression stage of carcinogen-induced tumors in rats ^{(9) (11)}.

Following oral administration, D-limonene is absorbed rapidly and metabolized to perillic acid (PA), dihydroperillic acid (DPA), limonene1,2-diol, and uroterpenol. D-Limonene metabolites distribute throughout the body to all sites, including adipose tissue, and are eliminated as glucuronide metabolites in the urine ^{(1) (2) (10)}.

Reported: Nausea, vomiting, diarrhea ⁽¹⁾
Case Report: Contact Dermatitis ⁽¹²⁾

None known

Vigushin DM, et al. Phase I and pharmacokinetic study of d-limonene in patients with advanced cancer. Cancer Research Campaign Phase I/II Clinical Trials Committee. Cancer Chemother Pharmacol 1998;42:111-7.
A phase I pharmacokinetic study was conducted with doses ranging from 500-12000 mg/m²/day. A single tumor response was documented in a breast cancer patient at the 8000 mg/m²/day dose level. The investigators conducted a small phase II study with 10 additional breast cancer patients but no additional tumor response was noted. Side effects include nausea, vomiting, and diarrhea. Additional studies are necessary to establish efficacy of D-limonene.